Process for manufacturing compositions containinig ciprofloxacin and hydrocortisone

ABSTRACT

This invention is directed toward a method of preparing a topical composition comprising ciprofloxacin and hydrocortisone. The method involves dispersing hydrocortisone with lecithin for greater than 45 minutes prior to combining hydrocortisone with the balance of the composition.

[0001] This application claims priority to U.S. Provisional Application,Ser. No. 60/220,865, filed Jul. 26, 2000.

1. BACKGROUND OF THE INVENTION

[0002] The present invention relates to topically administrableophthalmic and otic pharmaceutical compositions. In particular, thisinvention relates to a process for manufacturing compositions comprisingciprofloxacin, hydrocortisone and lecithin.

2. DESCRIPTION OF RELATED ART

[0003] U.S. Pat. No. 5,843,930 discloses topically administrableophthalmic and otic compositions comprising (a) ciprofloxacin in aqueoussolution in an amount effective for antibacterial action; (b) anon-ionic viscosity augmenter unaffected by pH and ionic level, saidviscosity augmenter being present in an amount effective for augmentingthe viscosity of the composition to a viscosity greater than that ofwater, said viscosity augmenter being at least 85% hydrolyzed polyvinylalcohol; (c) a non-ototoxic preservative present in an amount effectivefor antibacterial action the preservative being benzyl alcohol; (d)water sufficient to produce an aqueous composition; (e) hydrocortisonein aqueous suspension in an amount effective for anti-inflammatoryaction; (f) lecithin in an amount effective for enhancing suspension ofother constituents in the compositions; and (g) polysorbate ranging frompolysorbate 20 to 80 in an amount effective for spreading thepreparation on a hydrophobic skin surface to the site of infection orinflammation.

[0004] According to the '930 patent, the compositions comprisingciprofloxacin and hydrocortisone contain polyvinyl alcohol in an amounteffective for augmenting the viscosity of the composition to a viscositygreater than that of water and suspending other constituents of thecomposition. To allow a ciprofloxacin preparation to be administered indrops from a medicine dropper and to flow by gravity to and remain ordeposit in an effective amount at a selected area, aviscosity-augmenting agent that would also serve to suspendhydrocortisone was desirable. For compatibility with ciprofloxacinhydrochloride solubility, viscosity-augmenting agents were preferablynon-ionic and unaffected by pH and ionic level. See Col., 8, lines 13-31of the '930 patent.

[0005] Polyvinyl alcohol was selected for its ability to produce asuitable viscosity and a high ability to suspend hydrocortisone inaqueous preparations. See the '930 patent at Col. 8, lines 32-37. Theaddition of lecithin to the composition enhanced the efficacy ofpolyvinyl alcohol in suspending hydrocortisone in aqueous preparationswith ciprofloxacin hydrochloride and other components. See the '930patent at Col. 8, line 64-Col. 9, line 12.

[0006] The '930 patent discloses a process for manufacturingcompositions containing ciprofloxacin and hydrocortisone in Example 5 atColumn 5, lines 27-67. According this manufacturing process, polyvinylalcohol, lecithin, benzyl alcohol and acetic acid are sequentially addedto prepare a first stock solution. Separately sodium chloride and sodiumacetate are dissolved in water to form a second stock solution. A thirdstock solution is prepared by dissolving polysorbate 20 and dispersinghydrocortisone in water. Finally, ciprofloxacin is either added to thefirst stock solution or ciprofloxacin is prepared as a fourth stocksolution by dissolving ciprofloxacin, acetic acid and sodium acetate toform a ciprofloxacin stock solution. After the first and second stocksolutions are combined, the ciprofloxacin stock solution is added to thecombined solution. Finally, the third stock solution polysorbate 20 andhydrocortisone is mixed with the remaining batch volume.

[0007] A suspension composition's physical stability can be measured bytwo common methods. First, the resuspendability of a composition can bemeasured by allowing a homogeneous to remain standing in a cylindricalcontainer for a period of time, then determining the number ofinversions of the cylindrical container necessary to resuspend anysediment that form while the composition was standing. Second, the rateof settling can be measured by allowing a homogeneous suspensioncomposition to remain standing for a period of time, then observing theheight of sedimentation visible in a sample contained in a cylinder.Larger sedimentation heights indicate less separation with lesssupernatant liquid. Both measures of physical stability are important. Acomposition that is very easy to redisperse but that settles too quicklycan be difficult to manufacture. Suspension compositions must remainwell dispersed during processing and filling operations while commercialsupplies are prepared in order to insure uniform products.

SUMMARY OF THE INVENTION

[0008] The present invention provides ciprofloxacin and hydrocortisonecompositions that have excellent physical stability. The compositionsare prepared by dispersing for greater than 45 minutes hydrocortisonewith lecithin and optionally a polysorbate surfactant prior to combininghydrocortisone with the remainder of the composition. Among otherfactors, the present invention is based upon the finding that a specificorder of addition of ingredients in compositions containingciprofloxacin, hydrocortisone, a preservative, a non-ionic surfactant, abuffer, a tonicity agent, lecithin, polyvinyl alcohol and water canprovide compositions with excellent physical stability. Compositionsprepared by dispersing hydrocortisone with lecithin prior to mixinghydrocortisone with the balance of ingredients in the compositions havesuperior physical stability compared to those prepared by dispersinghydrocortisone with only a polysorbate surfactant prior to adding thehydrocortisone ingredient to the balance of the composition.

DETAILED DESCRIPTION OF THE INVENTION

[0009] Unless otherwise indicated, all ingredient concentrations arelisted as percent (w/w).

[0010] Ciprofloxacin is present in the compositions of the invention inan amount effective for anti-bacterial action. Such amounts range fromabout 0.01-1%, preferably from about 0.1-0.5%, and most preferably about0.2%. Compositions of the present invention also comprise hydrocortisoneas an anti-inflammatory agent. Hydrocortisone is present in an amounteffective for anti-inflammatory action. Such amount typically rangesfrom about 0.1-3%, preferably about 0.1-2%, and most preferably about1%. Particularly for ophthalmic use, small particle sizes are preferred.As used herein, “micronized” hydrocortisone means hydrocortisoneparticles having an average particle size ≦10 μm (based on surface area(dsn)). If the particle size of the hydrocortisone raw material asreceived from the supplier is unsatisfactory, one or more known sizingtechniques, such as ball milling or micronizing, can be used to adjustthe particle size into the desired range.

[0011] To prevent contamination by microorganisms and provide areasonable shelf-life, the compositions of the present invention includea preservative. Acceptable preservatives are required to cause no orinsignificant ototoxicity, sensitization or irritation of the ear.Additionally, the preservative must be jointly soluble withciprofloxacin in water over a pH range of approximately pH 3-6. The mostpreferred preservative is benzyl alcohol, which is typically present inan amount from about 0.1-3%, preferably about 0.1-2%, and mostpreferably about 0.9%.

[0012] A tonicity adjusting agent is preferably contained in an amountsufficient to cause the composition to be approximately isotonic, thatis an amount effective to adjust the tonicity of the composition fromabout 150-800 mOsm, preferably 200-600 mOsm. A preferredtonicity-adjusting agent is sodium chloride.

[0013] A buffering agent is desirable for the compositions of thepresent invention. The preferred buffering system is an acetate buffercomprising acetic acid and sodium acetate. Amounts of sodium acetate andacetic acid effective to buffer the preparation in a pH range of about4.0-5.3, preferably about 4.4-4.9 and most preferably about 4.7, rangefrom about 0.1-3% of sodium acetate and from about 0.01-10% of aceticacid. Preferably the amount of sodium acetate is from about 0.1-2% andmost preferably about 0.6-0.7%. Preferably the amount of sodium acid isabout 0.1-5% and most preferably about 0.2-0.3%. Sodium acetate ispreferably used in the form of sodium acetate trihydrate and acetic acidis preferably used in the form of glacial acetic acid.

[0014] To allow the compositions of the present invention to wet andspread on the skin surface at the site of infection or inflammation inthe ear canal, a non-ionic surfactant is desirable. The surfactantsknown as polysorbates, in particular polysorbates 20 to 80, arepreferred. Such polysorbates are commercially available under thetradename Tween from ICI Americas, Inc. Most preferred is polysorbate20. The amount of polysorbate surfactant contained in the compositionsof the present invention generally ranges from about 0.01-2%, preferablyabout 0.05-1%, and most preferably about 0.1%.

[0015] To help maintain or improve the physical stability of thesuspension composition of the present invention, lecithin or a lecithinderivative is added. Lecithins from natural/vegetative (e.g., egg or soylecithin) and synthetic origins are known. The primarily type oflecithin is phosphatidylcholine (PC). Other types of lecithins includephosphatidylglycerol; phosphatidylinositol; sphingomyelin; andphosphatidylethanolamine. Derivatives of lecithin with saturated andunsaturated fatty acid side chains on PC, are also known, including:distearoylphosphatidyl choline; dipalmitoylphosphatidyl choline; anddimirystoylphosphatidyl choline. As used herein, “lecithin” includessuch derivatives of lecithin. Preferably, the lecithin ingredientcomprises at least 75% PC.

[0016] Commercially available grades of soy lecithins include a fullyhydrogenated soy lecithin comprising 90% phosphatidylcholine availableunder the tradename Phospholipon 90H from American Lecithin Company anda soy lecithin comprising 75% phosphatidylcholine available under thetradename Lipoid-S75 from Vernon Walden, Inc. The amount of lecithincontained in the compositions of the present invention depends primarilyon the concentration of insoluble ingredients in the compositions. Theamount of lecithin in the compositions of the present inventiongenerally ranges from about 0.01-5%, preferably about 0.01-2% and mostpreferably is about 0.15%.

[0017] In addition to the excipients mentioned above, the ciprofloxacinand hydrocortisone compositions of the present invention optionallycomprise polyvinyl alcohol as a viscosity-augmenting agent. Thepolyvinyl alcohol contained in the composition of the present inventionshould be at least 85% hydrolyzed, with grades ranging from 85%hydrolyzed to 99+% hydrolyzed being suitable. Most preferred is an 88%hydrolyzed grade of polyvinyl alcohol, such as that commerciallyavailable as Airvol 205S from Air Products and Chemicals, Inc. Theamount of polyvinyl alcohol ingredient in the compositions of thepresent invention is preferably an amount effective to cause thecomposition to have a viscosity ranging from about 2-8 cps (whenmeasured at room temperature using a Brookfield Viscometer set at 30 rpmand a CP 42 spindle). Preferably, the polyvinyl alcohol ingredient ispresent in an amount sufficient to cause the composition's viscosity tobe from about 3-7 cps.

[0018] The compositions of the present invention are prepared in aspecific manner. It is essential that the hydrocortisone ingredient isfirst mixed with lecithin for greater than 45 minutes prior to combiningthe hydrocortisone ingredient with the remainder of the composition.Preferably, hydrocortisone is mixed with both lecithin and a polysorbate20 to 80 surfactant before combining hydrocortisone with the remainderof the composition. The presence of the polysorbate surfactant providesa lower viscosity slurry than simply mixing hydrocortisone and lecithinalone. The lower viscosity achieved by the addition of the polysorbatesurfactant makes processing easier.

[0019] As mentioned above, hydrocortisone is preferably sized to achievedesirable particle sizes. The hydrocortisone ingredient in thecompositions of the present invention can be sized in the presence oflecithin and optionally a polysorbate 20 to 80 surfactant. If thehydrocortisone ingredient is sized prior to mixing with lecithin, thenthe mixing with lecithin step must occur prior to combininghydrocortisone with the remainder of the ciprofloxacin andhydrocortisone composition. Particle sizing techniques are known in theart and include ball milling, homogenization and micronization. As usedherein, “mixing” includes simple mixing as well as sizing procedures.

[0020] The lecithin ingredient should be dispersed in water at atemperature above the phase transition temperature for the chosen gradeof lecithin. In the case of phospholipon 90H, the phase transitiontemperature is approximately 51° C. Therefore, Phospholipon 90H ispreferably dispersed at a temperature of approximately 65-70° C. Apolysorbate surfactant, if present, can be dispersed simultaneously withlecithin or added before or after lecithin is fully dispersed. After thepolysorbate surfactant and lecithin are dispersed, hydrocortisone(preferably micronized) is then dispersed. The hydrocortisone ispreferably added after removing the lecithin dispersion from heat, butbefore the lecithin dispersion cools to room temperature. Thehydrocortisone ingredient is preferably mixed with the lecithindispersion for approximately 6 to 18 hours or more, and most preferablyabout 12 hours, before being added to the remainder of theciprofloxacin/hydrocortisone composition.

[0021] In a separate vessel, ciprofloxacin is dissolved in water with anacetate buffer, then the benzyl alcohol preservative, sodium chloridetonicity adjusting agent and the polyvinyl alcohol viscosity augmenterare sequentially added, with each ingredient being dispersed ordissolved prior to the addition of the next. Although it is possible toadd all of these ingredients simultaneously rather than sequentiallyprovided that the vessel contains a sufficient amount of water,sequentially mixing and dispersing is preferred.

[0022] After the ciprofloxacin solution has been prepared, it iscombined with the hydrocortisone slurry then the pH is adjusted withNaOH or HCl and the batch volume is adjusted with purified water.

[0023] The ciprofloxacin/hydrocortisone compositions described above arepreferably prepared as follows.

[0024] 1. Add approx. 5-50% of the total batch volume of purified waterto a compounding vessel and heat to a temperature above the transitiontemperature of the chosen grade of lecithin (in the case of Phospholipon90H the preferred temperature is approximately 65-70° C.).

[0025] 2. Using a magnetic stir bar, disperse 50% of the total requiredamount of lecithin (preferably, Phospholipon 90H) and 50% of the totalrequired amount of surfactant (preferably polysorbate 20) into theheated water of Step 1 until uniformly dispersed (generally about 10-20min.). Remove from heat.

[0026] 3. Add the hydrocortisone (preferably micronized hydrocortisone)before the dispersion of Step 2 cools to room temperature and mix forapproximately 12 hrs. (i.e., overnight).

[0027] 4. Prepare a ciprofloxacin solution by adding the followingcomponents in order and mix well allowing each to disperse or dissolvebefore adding the next: the remaining 50% of the total amount oflecithin (at elevated temperature), the remaining 50% of the totalamount of surfactant, the preservative, the buffer (e.g., glacial aceticacid then sodium acetate (trihydrate)), ciprofloxacin, and thetonicity-adjusting agent, and optionally polyvinyl alcohol (from stocksolution).

[0028] 5. Prepare a stock solution of polyvinyl alchohol in purifiedwater. The stock solution is preferably prepared at a polyvinyl alcoholconcentration of about 0.5 or 1.0 % and preferably prepared at 90-95° C.(for easier and faster solution preparation) then cooled to roomtemperature.

[0029] 6. Add the hydrocortisone dispersion of Step 3 to theciprofloxacin solution of Step 4 (while mixing), then mix in therequired amount of polvinyl alcohol stock solution.

[0030] 7. QS to 90% with purified water

[0031] 8. Measure and adjust pH to about 4.7 with 1N NaOH and/or 1N HCl,then QS to 100% with purified water.

EXAMPLES

[0032] The following examples are presented to illustrate furthervarious aspects of the present invention, but are not intended to limitthe scope of the invention in any respect.

[0033] The formulations shown in Table 1 were prepared. TABLE 1FORMULATION # 1 2 3 4 Ciprofloxacin 0.2329* 0.2329* 0.2329* 0.2329*Hydrochloride, monohydrate Hydrocortisone, 1.0 1.0 1.0 1.0 micronizedBenzyl Alcohol 0.9 0.9 0.9 0.9 Polyvinyl Alcohol 2.0 0.05 0.1 — 99%hydrolyzed (AIRVOL 125) NaCl 0.9 0.9 0.9 0.9 Sodium Acetate, 0.68 0.680.68 0.68 trihydrate Glacial Acetic Acid 0.255 0.255 0.255 0.255Lecithin 0.15 0.15 0.15 0.15 (Phospholipon 90H) Polysorbate 20 0.10 0.100.10 0.10 NaOH/HCl pH 4.7 pH 4.7 pH 4.7 pH 4.7 Purified Water QS 100 QS100 QS 100 QS 100

[0034] Formulation #1 was prepared in four pre-mix portions, which werefinally combined in a single mixing tank as follows:

[0035] a. Polyvinyl alcohol and lecithin are dissolved in purifiedwater, which has been heated to 90-95° C. This solution is cooled to 50°C. before benzyl alcohol is added and dispersed. The solution is cooledto room temperature.

[0036] b. Hydrocortisone is dispersed in a mixture of polysorbate 20 andpurified water in a second container. The mixture is homogenized toassure uniform distribution of individual particles in the pre-mix.

[0037] c. The sodium acetate and glacial acetic acid are dissolved inpurified water in a third container, Ciprofloxacin HCl is then added anddissolved in this buffer.

[0038] d. Sodium chloride is dissolved in purified water in a fourthcontainer.

[0039] The contents of each container are pumped through a polishingfilter into the mixing tank in the order given. If necessary, 1N NaOH or1N HCl is added to adjust pH to 4.7, prior to bringing to final volume.

[0040] Formulation #2 was prepared in three different ways.

[0041] Formulation #2A was prepared as follows:

[0042] Milling Slurry (For a 200 ml formulation batch)

[0043] 1. Weigh out and add all of the specified amount ofhydrocortisone to a 30 ml polypropylene milling bottle.

[0044] 2. Weigh out and add 50% of the specified amount of 1%Polysorbate 20 stock solution and 50% of the specified amount oflecithin (phospholipon 90H) and heat to approximately 65-70° C. todisperse the lecithin homogeneously.

[0045] 3. Transfer the solution of polysorbate 20 and phospholipon 90 Hmixture to the milling bottle.

[0046] 4. Weigh out and add 75.0 g of zirconia-Y beads (3 mm) to themilling bottle.

[0047] 5. Shake well to wet the hydrocortisone powder

[0048] 6. Ball mill slurry for 18 hours at 55 rpm

[0049] Vehicle:

[0050] 1. Tare a compounding vessel containing a stirring bar

[0051] 2. Weigh and add the specified amount of polyvinyl alcohol stocksolution

[0052] 3. Add purified water to approximately 20% of the total batchvolume and heat to approximately 65-70° C.

[0053] 4. Weigh and add the remaining amount of lecithin (phospholipon)and disperse by simple stirring at 65-70° C.

[0054] 5. Allow to cool to room temperature with stirring

[0055] 6. Add the following (in order) with stirring allowing each todissolve/disperse completely before addition of the next: benzylalcohol, glacial acetic acid, sodium acetate, ciprofloxacin HCl, sodiumchloride

[0056] 7. Transfer the ball milled slurry ofhydrocortisone/lecithin/polysorbate 20 mixture through a suitable sieveinto the compounding vessel rinsing the beads well with purified water.

[0057] 8. Weigh and add the remaining amount of 1% polysorbate 20 to thecompounding vessel with stirring.

[0058] 9. QS to 95% of total batch volume with purified water

[0059] 10. Check and adjust pH to target pH of 4.7 with 1N sodiumhydroxide and/or 1N hydrochloric acid.

[0060] 11. QS to 100% (200 ml) with purified water and allow to mixwell.

[0061] Formulation #2B was prepared according to the procedure used toprepare Formulation #2A except that the hydrocortisone slurry was madeas follows:

[0062] 1. Weigh out and add all of the required 1% polysorbate 20 stocksolution, add all of the required lecithin (Phospholipon 90H) and heatto approximately 65-70° C. to disperse (with stir bar) the lecithinhomogeneously.

[0063] 2. Add all of the required amount of micronized hydrocortisoneand mix the hydrocortisone slurry for 45 minutes using a magnetic stirbar.

[0064] The vehicle was prepared according to the procedure used toprepare the vehicle for Formulation #2A except that the polyvinylalcohol stock solution was added in step 6 (after sodium chloride).

[0065] Formulation #2C was prepared according to the procedure used toprepare Formulation #2B except that there is no heating in thepreparation of the hydrocortisone slurry. The lecithin is dispersed atroom temperature instead of approximately 65-70° C.

[0066] A preferred method for making Formulation #2 is provided below:

[0067] 1. Tare a compounding vessel with stirring bar.

[0068] 2. Add 50% of total batch weight of purified water to thecompounding vessel.

[0069] 3. Heat the purified water and maintain at approximately 65-70°C.

[0070] 4. Add 50% of the batch weight of Phospholipon 90H into thecompounding vessel containing water at 65-70° C. Maintain thetemperature for 10-20 minutes while stirring to make sure a homogenousdispersion of Phospholipon 90H is achieved.

[0071] 5. Remove from heat and add 50% of the batch weight ofpolysorbate 20 (1% stock solution) to the Phospholipon 90H aqueousdispersion.

[0072] 6. Add hydrocortisone powder into the compounding vessel andallow mixing by simple stirring for an overnight period (approx. 12hours).

[0073] 7. Add the remaining components of the formula into step 6,allowing each component to mix or dissolve well by stirring: benzylalcohol, glacial acetic acid, sodium acetate (trihydrate), ciprofloxacinhydrochloride, sodium chloride, remaining Phospholipon 90H, remainingpolysorbate 20 and polyvinyl alcohol (Airvol 125) as a stock solution.

[0074] 8. QS to 90% of the batch weight with purified water.

[0075] 9. Measure and adjust pH to 4.7 with 1N NaOH or 1N HCl, ifnecessary.

[0076] 10. QS to 100% of the batch weight with purified water and stiruntil homogeneous.

[0077] Formulation #3 was prepared in two different ways.

[0078] Formulation #3A was prepared using the same procedure used forFormulation #2A.

[0079] Formulation #3B was prepared using the same procedure used forFormulation #2B.

[0080] Formulation #4 was prepared in eleven different ways.

[0081] Formulation #4A was prepared using the same procedure used toprepare Formulation #1:

[0082] Part I:

[0083] 1. Tare a compounding vessel with a stirring bar.

[0084] 2. Weigh and add the specified amount of lecithin.

[0085] 3. Add a small amount of purified water so the volume isapproximately 25% of the total batch volume.

[0086] 4. Heat to 9° C.

[0087] 5. Allow the mixture to cool to room temperature and add thebenzyl alcohol

[0088] 6. Mix until homogeneous.

[0089] 7. Add the following components allowing each to dissolve beforeadding the next: glacial acetic acid, sodium acetate, ciprofloxacin andsodium chloride.

[0090] 8. Mix well.

[0091] Part II:

[0092] 1. In another beaker add the polysorbate 20 and hydrocortisonetogether and mix well.

[0093] Part III:

[0094] 1. Add Part II into Part I and mix well.

[0095] 2. QS to 95% with purified water.

[0096] 3. Measure and adjust pH with 1N NaOH and/or 1N HCl to the targetpH of 4.7.

[0097] 4. QS to 100% of batch volume with purified water.

[0098] Formulation #4B was prepared using the following method:

[0099] 1. Weigh out and add the specified amount of hydrocortisone to a30 ml polypropylene milling bottle.

[0100] 2. Weigh out and add 50% of the specified amount of 1%polysorbate 20 stock solution.

[0101] 3. Weigh out and add 75.0 g of zirconia-Y beads (3 mm) to themilling bottle.

[0102] 4. Shake well to wet the hydrocortisone powder.

[0103] 5. Ball mill slurry for 18 hours at 55 rpm.

[0104] Vehicle:

[0105] 1. Tare an appropriate sized compounding vessel containing astirring bar.

[0106] 2. Weigh and add the specified amount of lecithin.

[0107] 3. Add purified water to approximately 20% of the total batchvolume.

[0108] 4. Heat with stirring to 90° C.

[0109] 5. Allow to cool to room temperature with stirring.

[0110] 6. Add the following (in order) with stirring allowing each todissolve/disperse completely before addition of the next: benzylalcohol, glacial acetic acid, sodium acetate, ciprofloxacin HCl, sodiumchloride

[0111] 7. Transfer the ball milled slurry through a suitable sieve intothe compounding vessel rinsing the beads well with purified water.

[0112] 8. Weigh and add the remaining amount of 1% polysorbate 20 to thecompounding vessel with stirring.

[0113] 9. Check and adjust pH to target pH of 4.7 with 1N sodiumhydroxide and/or 1N hydrochloric acid.

[0114] 10. QS to 100% (200 ml) with purified water and allow to mixwell.

[0115] Formulation #4C was prepared using the same procedure used forFormulation #4B except that the ball milling time for the hydrocortisoneslurry was extended from 18 hrs. to 72 hrs.

[0116] Formulation #4D was prepared using the following method:

[0117] 1. Weigh out and add the specified amount of hydrocortisone to a30 ml polypropylene milling bottle

[0118] 2. Weigh out and add 50% of the specified amount of 1%polysorbate 20 stock solution

[0119] 3. Weigh out and add 50% of the specified amount of sodiumchloride

[0120] 4. Add 75.0 g of zirconia-Y beads (3 mm) to the milling bottle

[0121] 5. Shake well to wet the hydrocortisone powder

[0122] 6. Autoclave the slurry for 30-35 minutes at 121° C.

[0123] 7. Ball mill slurry for 18 hours at 55 rpm

[0124] Vehicle:

[0125] 1. Tare an appropriate sized compounding vessel containing astirring bar.

[0126] 2. Weigh and add the specified amount of lecithin.

[0127] 3. Add purified water to approximately 20% of the total batchvolume.

[0128] 4. Heat with stirring to 90° C.

[0129] 5. Allow to cool to room temperature with stirring.

[0130] 6. Add the following (in order) with stirring allowing each todissolve/disperse completely before addition of the next: benzylalcohol, glacial acetic acid, sodium acetate, ciprofloxacin HCl,remaining 50% of sodium chloride

[0131] 7. Transfer the ball milled slurry into the compounding vesselthrough a suitable sieve rinsing the beads well with purified water.

[0132] 8. Weigh and add the remaining amount of 1% polysorbate 20 to thecompounding vessel with stirring.

[0133] 9. Check and adjust pH to target pH of 4.7 with 1N sodiumhydroxide and/or 1N hydrochloric acid.

[0134] 10. QS to 100% (200 ml) with purified water and allow to mixwell.

[0135] Formulation #4E was prepared using the following method:

[0136] Homogenization Slurry:

[0137] 1. Weigh out and add the specified amount of hydrocortisone to a50 ml beaker.

[0138] 2. Weigh out and add specified amount of 1% polysorbate 20 stocksolution.

[0139] 3. Homogenize the mixture for 30 minutes using a POLYRONhomogenizer at setting 6.

[0140] Vehicle:

[0141] 1. Tare an appropriate sized compounding vessel containing astirring bar.

[0142] 2. Weigh and add the specified amount of lecithin.

[0143] 3. Add purified water to approximately 20% of the total batchvolume.

[0144] 4. Heat with stirring to 90° C.

[0145] 5. Allow to cool to room temperature with stirring.

[0146] 6. Add the following (in order) with stirring allowing each todissolve/disperse completely before addition of the next: benzylalcohol, glacial acetic acid, sodium acetate, ciprofloxacin HCl, sodiumchloride

[0147] 7. Transfer the homogenized slurry into the compounding vesselrinsing the beaker well with purified water.

[0148] 8. QS to 95% of the total batch volume using purified water.

[0149] 9. Check and adjust pH to target pH of 4.7 with 1N sodiumhydroxide and/or 1N hydrochloric acid.

[0150] 10. QS to 100% (200 ml) with purified water and allow to mixwell.

[0151] Formulation #4F was prepared using the same procedure used forFormulation #2A except that the slurry was ball milled for 72 hrs.instead of 18 hrs.

[0152] Formulation #4G was prepared using the same procedure used forFormulation #2A.

[0153] Formulation #4H was prepared using the same procedure used forFormulation #2A except that no polysorbate 20 was used in the millingslurry. All of the required amount of polysorbate 20 was added in Step 8of the vehicle preparation.

[0154] Formulation #4I was prepared using the same procedure used forFormulation #2B except that the slurry was mixed overnight (approx. 12hrs.) instead of 45 minutes.

[0155] Formulation #4J was prepared using the same procedure used forFormulation #4I except that the hydrocortisone slurry did not containany polysorbate 20. All of the required amount of polysorbate 20 wasadded in Step 8 of the vehicle preparation.

[0156] Formulation #4K was prepared using the same procedure used forFormulation #2B.

[0157] The table below summarizes the differences in the procedures usedto make the formulations. TABLE 2 Formulation # Preparation 1, 4A HC +PS20 mixed well 2A, 3A, 4G HC + 50% of lecithin + 50% of PS20; baIlmilled for 18 hrs. 2B, 3B, 4K HC + 100% of lecithin + 100% of PS20;lecithin dispersed at 70° C. by simple mixing for 45 min. 2C Same as 2Bbut lecithin dispersed at R.T. 4B HC + 50% of PS20; ball milled for 18hrs. 4C Same as 4B, but ball milled for 72 hrs. 4D Autoclaving HC + 0.3%NaCl + 50% of PS20, then ball milling for 18 hrs. 4E HC + PS20homogenized for 30 min. 4F Same as 2A, but ball milled for 72 hrs. 4HHC + 50% of lecithin; ball milled for 18 hrs. 4I Same as 2B, but mixed12 hrs. 4J HC + 100% of lecithin; lecithin dispersed at 70° C. by simplemixing for ˜12 hrs.

[0158] The physical stability of suspension formulations is commonlymeasured in two ways: resuspendability is assessed by measuring thenumber of inversions (also called strokes) required to redispersesedimentation which forms after a sample stands undisturbed for a periodof time; and rate of settling is assessed by observing the height inmillimeters of the column of sedimentation visible in a sample containedin a cylinder after shaking and then standing for a period of time. Inorder to record the rate of settling results, the following codes areused (in order of increasing turbidity): C: Clear Supernatant Phase, LM:Light Milky Phase (less dense than Homogeneous phase), H: HomogenousPhase (initial homogeneous phase), D: Dense Phase (more dense thanHomogeneous Phase), S: Sediment. Larger sedimentation heights indicateless separation with less supernatant liquid and less compaction ofsedimentation. The physical stability of Formulations 1-4K was evaluatedaccording to the methods described above and the results are shown inTables 3 and 4. TABLE 3 FORMULATION # 1 2a 2B 2C 3A 3B Resuspendability3 1 1 1 1 3 Real Time: # of (2 days (7 days (4 days (4 days (9 days (4days inversions settling) settling) settling) settling) settling)settling) Accelerated (10 min. @ 500 rpm): # of inversions 8 2 2, 3 3, 35, 6 2, 2 wrist shaking (sec.) <1 <1, <1 <1, <1 <1, <1 <1, <1 <1, <1Accelerated (30 min. @ 500 rpm): # of inversions — — 3, 3 2, 2 — 3, 4Viscosity (cps) 6.14, 3.16, — — — — (30 rpm, cp 42 5.90 3.26 spindle @250° C.) Osmolality 556, — 546, 535, 540, 543, (mOsm/kb) 552 538 534 530537 FORMULATION # 4A 4B 4C 4D 4E 4F Resuspendability 1 1 1 1 1 1 RealTime: # of (15 days (15 days (15 days (15 days (15 days (15 daysinversions settling) settling) settling) settling) settling) settling)Accelerated (10 min. @ 500 rpm): # of inversions 2, 3 1, 2 — 3, 4 2, 34, 4 wrist shaking (sec.) <1, <1 <1, <1 — <1, <1 <1, <1 <1, <1Accelerated (30 min. @ 500 rpm): # of inversions — — — — — — Viscosity(cps) — — — — — — (30 rpm, cp 42 spindle @ 250° C.) Osmolality 537, 532,— 536, 534, 534, (mOsm/kb) 536 536 543 532 538 FORMULATION # 4G 4H 4I 4J4K Resuspendability 1 1 1 1 1 Real Time: # of (9 days (9 days (2 days (4days (4 days inversions settling) settling) settling) settling)settling) Accelerated (10 min. @ 500 rpm): # of inversions 4, 4 — 1 6, 73, 2 wrist shaking (sec.) <1, <1 — <1 <1, <1 <1, <1 Accelerated (30 min.@ 500 rpm): # of inversions — — 1, 2 6, 5 3, 3 Viscosity (cps) — — 3.96,— — (30 rpm, cp 42 4.00 spindle @ 250° C.) Osmolality 540, — 549, 543,535, (mOsm/kb) 545 546 557 541

[0159] TABLE 4 Rate of Settling #1 #2A #2B #2C #3A #3B Initial   0-10  0-10   0-10   0-10   0-10   0-10 ml. H ml: H ml: H ml. H ml: H ml. H 5minutes   0-10   0-10   0-10   0-5   0-10   0-2.5 ml: H ml: H ml: H ml:D ml. H ml: S   5-10   2-10 ml: LM ml. LM 10 minutes   0-10   0-10  0-10   0-29   0-10   0-2 ml: H ml: H ml: H ml: D ml. H ml: S 2.9-10  2-10 ml: LM ml. LM 15 minutes   0-10   0-10   0-10   0-2.2   0-10  0-1.8 ml: H ml: H ml. H ml: D ml. H ml: S 2.2-10  18-10 ml: LM ml. LM20 minutes   0-10   0-10   0-9.9   0-2   0-10   0-1.6 ml. H ml. H ml: Hml: D ml. H ml: S 9.9-10   2-10 1.6-10 ml: C ml: LM ml. LM 30 minutes  0-10   0-10   0-9.7   0-2   0-10   0-1.6 ml: H ml: H ml. H ml: D ml: Hml: S  97-10   2-9.9 1.6-10 ml: C ml: LM ml: LM 45 minutes   0-8   0-10  0-9.3   0-19   0-10   0-1.6 ml: D ml. H* ml: H ml: S ml: H* ml: S  8-10  93-10  19-10 1.6-10 ml: LM ml: C ml. LM ml: LM 1 Hour   0-5  0-10   0-9   0-2   0-10   0-1.7 ml: S ml. H ml: H ml: S ml: H ml: S  5-8   9-10   2-10 1.7-10 ml: LM ml: C ml. LM ml: LM   8-10 ml. C 2Hours   0-2.5   0-10   0-68   0-3   0-10   0-1.7 ml: S ml. H ml: H ml: Sml: H ml: S  25-10  68-1  31-10 1.7-10 ml: LM ml: C ml. LM ml: LM 3Hours   0-2.4   0-9.9   0-5.2   0-28   0-9.9   0-2 ml: S ml. H ml: D ml:S ml: H ml: S  24-10 9.9-10 5.2-10  28-10 9.9-10 2.1-10 ml: LM ml. C ml:C ml. LM ml: LM ml: LM 4 Hours   0-23   0-9.9   0-4.7   0-2.6   0-9.9  0-20 ml: S ml. H ml: D ml: S ml: H ml: S  23-10 9.9-10 4.7-10  26-109.9-10 2.0-10 ml: C ml. C ml: C ml. LM ml: C ml: LM 5 Hours   0-2.1  0-9.9   0-4.2   0-25   0-9.9   0-1.9 ml: S ml. H** ml: D ml: S ml: H**ml: S  21-10 9.9-10 4.2-10  25-10 9.9-10 1.9-10 ml: C ml. C ml: C ml. LMml: C ml: C 1 Day   0-1.9   0-94   0-2.3   0-2   0-9.4   0-1.6 ml: S ml.H ml: S ml: S ml: H ml: S 1.9-10 9.4-10 2.3-10   2-10 9.4-10 1.6-10 ml:C ml. C ml: C ml: C ml: C ml: C Time #4A #4B #4C #4D #4E #4F Initial  0-10   0-10   0-10   0-10   0-10   0-10 ml: H ml: H ml: H ml. H ml: Hml. H 5 minutes   0-2   0-9.7   0-9.6   0-9.7   0-2   0-10 ml: S ml: Dml: D ml: D ml. S ml: H   2-7  97-10 9.6-10 9.7-10   2-7 ml: D ml LM ml:LM ml: LM ml: D   7-10   7-10 ml: LM ml: LM 10 minutes   0-2   0-9.4  0-9.5   0-9.4   0-2.2   0-10 ml: S ml: D ml: D ml: D ml. S ml: H  2-10 9.4-10 9.5-10 9.4-10  2.2-10 ml. LM ml: LM ml: LM ml: LM l LM 15minutes   0-1.9   0-9.4   0-93   0-9.4   0-1.9 0.9-9 ml: S ml: D ml. Dml: D ml. S ml: H  19-10  94-10  93-10 9.4-10 1.9-10  99-10 ml LM ml. LMml. LM ml: LM ml: LM ml. LM 20 minutes   0-1.8   0-9.4   0-93   0-93  0-1.8   0-9.9 ml. S ml. D ml: D ml: D ml: S ml: H 1.8-10  94-10 9.3-109.3-10  18-10 9.9-10 ml. LM ml: LM ml: LM ml: LM ml. LM ml. LM 30minutes   0-1.5   0-9.1   0-9   0-92   0-1.6   0-9.9 ml: S ml: D ml. Dml: D ml: S ml: H 1.5-9.6  91-10   0-9 9.2-10 1.6-9.8 9.9-10 ml: LM ml.LM ml: LM ml: LM ml: LM ml: LM  96-10 9.8-10 ml: C ml: C 40 minutes  0-1.5   0-9   0-8.5   0-9   0-15   0-9.9 ml: S ml. D ml: D ml: D ml: Sml: H 1.5-95   9-10  85-10   9-10  15-97 9.9-10 ml: LM ml. LM ml: LM ml.LM ml: LM ml: LM  95-10 9.7-10 ml. C ml. C 1 hour   0-15   0-86   0-8  0-85   0-1.5   0-9.9 ml: S ml. D ml. D ml: D ml: S ml: H 1.5-9.48.6-10   8-10  85-10 1.5-9.6 9.9-10 ml: LM ml. LM ml: LM ml. LM ml. LMml: LM  94-10 9.6-10 ml. C ml. C 2 hours   0-15   0-7.5   0-55   0-7.4  0-1.5   0-99 ml: S ml. D ml: D ml: D ml: S ml: H  15-8.6  75-10 5.5-107.4-10 1.5-9.1 9.9-10 ml: LM ml. LM ml: LM ml. LM ml. LM ml: LM 8.6-109.1-10 ml: C ml: C 3 hours   0-1.7   0-6.5   0-5.4   0-6.3   0-1.5  0-9.8 ml: S ml. D ml: D ml: D ml: S ml: H 1.7-7.9  65-10 5.4-10 6.3-101.5-8.7 9.8-10 ml: H ml. H ml: H ml. H ml: LM ml: C  79-10 8.7-10 ml: Cml: C 4 hours   0-1.8   0-5.5   0-4.4   0-5.3   0-1.8   0-9.8 ml: S ml.D ml: D ml: D ml: S ml: H 1.8-7.3  55-10 4.4-10  53-10 1.8-83 9.8-10 l:H ml. LM ml: LM ml. MH ml: LM ml: C 7.3-10 8.3-10 ml C ml: C 1 Day  0-25   0-27   0-2.5   0-2.8   0-3.3   0-8.9 ml: S ml. S ml: S ml: Sml: S ml: H 2.5-10 2.7-10 2.5-10  28-10 3.3-10  89-10 ml: C ml: LM ml: Cml: LM ml: C ml: C Time #4G #4H #4I #4J #4K Initial   0-10   0-10   0-10  0-10   0-10 ml. H ml: H ml: H ml. H ml: H 5 minutes   0-10   0-10  0-10   0-10   0-27 ml: H ml: H ml: H ml: H ml. S 2.7-10 ml: LM 10minutes   0-10   0-10   0-10   0-10   0-2 ml: H ml: H ml: H ml: H ml. S  2-10 ml: LM 15 minutes   0-10   0-10   0-10   0-10   0-1.9 ml: H ml: Hml. H ml: H ml. S 1.9-10 ml: LM 20 minutes   0-10   0-10   0-10   0-10  0-1.7 ml. H ml. H ml: H ml: H ml. S 1.7-10 ml LM 30 minutes   0-10  0-10   0-10   0-10   0-1.6 ml: H ml: H ml. H ml: H ml: S 1.6-10 ml: LM45 minutes   0-10   0-10   0-10   0-10   0-1.7 ml: H* ml. H* ml: H ml: Hml: S 1.7-10 ml: LM 1 Hour   0-10   0-10   0-10   0-10   0-1.7 ml: H ml.H ml: H ml: H ml: S  17-10 ml: LM 2 Hours   0-10   0-10   0-99   0-99  0-21 ml: H ml. H ml: H ml: H ml: S  99-10 9.9-10 2.1-10 ml: C ml. Cml: LM 3 Hours   0-9.8   0-97   0-9.9   0-9.9   0-22 ml: H ml. H ml: Hml: H ml: S  98-10  97-10 9.9-10 9.9-10  22-10 ml: LM ml. LM ml: C ml. Cml: LM 4 Hours   0-98   0-9.7   0-9.9   0-99   0-2.1 ml: H ml. H ml: Hml: H ml: S 9.8-10 9.7-10 9.9-10 9.9-10 2.1-10 ml: LM ml. LM ml: C ml. Cml: LM 5 Hours   0-9.8   0-9.7   0-98   0-98   0-2 ml: H ml. H ml: H ml:H ml: S  98-10  97-10  98-10  98-10   2-10 ml: LM ml. LM ml: C ml. C ml:C 1 Day   0-95   0-8.9   0-9.0   0-8.5   0-1.7 ml: H ml. H ml: H ml: Hml: S  95-10  89-10   9-10  85-10 1.7-10 ml: C ml. C ml: C ml: C ml: C

[0160] As shown in Table 3, the formulations prepared according to themethod of the present invention (Formulation #'s 2A, 3A, 4F, 4G, 4H, 4Iand 4J) have resuspendability results approximately equivalent orsuperior to those prepared by other methods as comparative examples(Formulation #'s 1, 2B, 2C, 3B, 4A, 4B, 4C, 4D, 4E and 4K). As shown inTable 4, the formulations of the present invention have superior rate ofsettling results compared to the formulations of the comparativeexamples. See, for example, the data shown in Table 4 after 2 hours(which represents a target manufacturing time period for allowingpumping and filling final product packages with homogeneous suspensionformulations); the formulations of the present invention aresubstantially homogeneous after 2 hours but the formulations of thecomparative examples are not.

[0161] The invention has been described by reference to certainpreferred embodiments; however, it should be understood that it may beembodied in other specific forms or variations thereof without departingfrom its spirit or essential characteristics. The embodiments describedabove are therefore considered to be illustrative in all respects andnot restrictive, the scope of the invention being indicated by theappended claims rather than by the foregoing description.

We claim:
 1. A method of preparing a suspension composition comprisingciprofloxacin, hydrocortisone, lecithin, and excipients selected fromthe group consisting of preservatives; buffers; tonicity-adjustingagents; and pH-adjusting agents, wherein the method comprises the stepof dispersing for greater than 45 minutes hydrocortisone with lecithinand optionally a polysorbate surfactant to form a hydrocortisone slurryprior to combining hydrocortisone with any other excipients.
 2. Themethod of claim 1 wherein the suspension composition further comprisespolyvinyl alcohol as a viscosity-enhancing excipient.
 3. The method ofclaim 1 wherein the hydrocortisone is dispersed with lecithin and apolysorbate surfactant for about 6-18 hours prior to combining thehydrocortisone with any other excipients.